Thirty to 60% of patients with diabetes mellitus suffer from symptoms of gastropathy and gastroparesis, e.g. dyspepsia, pain, recurring nausea and vomiting and consequent malnutrition, impaired glycemic control, and diminished quality of life. Pathogenetic factors include systemic and myenteric neuropathy, which may lead to pylorospasm and reduced receptive relaxation of the fundus; smooth myopathy, which reduces contractility; and depletion of interstitial cells of Cajal (ICC), which leads to electrical dysrhythmias and reduced phasic contractions and contributes to impaired neuromuscular neurotransmission. ICC are also reduced in idiopathic gastroparesis. Current therapeutic approaches, which are frequently inadequate, include diet, jejunostomy or parenteral feeding, attention to blood glucose control, gastric decompression, reducing pyloric tone, and stimulation of residual gastric motor function with gastrokinetic drugs or electrical pacing. Importantly, recent data indicate that patients with reduced ICC tend to be refractory to medical therapy and respond poorly to electrical stimulation. Thus, patients suffering from gastroparesis would likely benefit from prevention of ICC depletion or replacement of the missing cells. In this project we will explore, in animal and in vitro models, the following approaches to prevent and restore ICC: We plan to examine whether treatments with insulin and other growth factors, which are reduced or ineffective in diabetes but are required for the long-term maintenance if ICC, could prevent or restore the loss of these cells in nonobese diabetic mice. Our second aim is to develop conditionally immortalized ICC and examine whether these cells can restore rhythmic electrical and contractile activity in organotypic cultures. Finally, we plan to isolate and characterize committed or multipotent precursors of ICC ("adult" stem cells), examine their developmental potential in vitro and in-vivo, and study their regulation and fate in mice with diabetic and nondiabetic gastroparesis. The proposed experiments could lead to novel treatment options to restore function that is lost in patients with diabetic or nondiabetic gastroparesis. Relevance to public health: Gastroparesis causes diminished quality of life in a significant proportion of patients with diabetes. Current therapy aims at stimulating residual function and is frequently inadequate. The goal of this project is to develop novel treatments that focus on restoring, or preventing the loss of, cells that are reduced in this disorder. [unreadable] [unreadable] [unreadable]